EP0055990B1 - Beta-lactam antibiotics, their preparation and use - Google Patents

Beta-lactam antibiotics, their preparation and use Download PDF

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Publication number
EP0055990B1
EP0055990B1 EP82100683A EP82100683A EP0055990B1 EP 0055990 B1 EP0055990 B1 EP 0055990B1 EP 82100683 A EP82100683 A EP 82100683A EP 82100683 A EP82100683 A EP 82100683A EP 0055990 B1 EP0055990 B1 EP 0055990B1
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Prior art keywords
ester
salt
max
group
hept
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EP0055990A1 (en
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David Francis Corbett
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • This invention relates the preparation of carbapenem derivatives, and to certain novel antibacterial carbapenem derivatives and compositions containing them.
  • European Patent Application Publication Number 0001628 discloses a group of synthetic antibacterial agents containing a 7-oxo-1-azabicyclo[3.2.0.]hept-2-ene ring system.
  • EP-A-1627 discloses a similar group of 7-oxo-1-azabicyclo[3.2.0.]hept-2-ene ring systems having a 1-hydroxyethyl substituent at C-6.
  • all compounds described in those specifications are racemic at-C-5 and can only be prepared by a very long synthetic sequence.
  • a new process has been discovered that enables new antibacterial agents to be prepared via the intermediacy of a thiol. These new antibacterial agents can be prepared by a relatively short reaction sequence from natural products and are produced as a desirable single optical isomer at C-5.
  • the present invention provides a process for the preparation of a compound of formula (I): and salts and esters thereof, wherein
  • the present invention also provides a compound of the formula (IA): and salts and esters thereof, wherein
  • a group of compounds of interest are those of the formula (IA) wherein R 22 is hydrogen, OS0 3 H or a pharmaceutically acceptable salt or a methyl or ethyl ester thereof, SR 3 , or OCONHR 3 where R 3 is a (C 1-4 )alkyl, benzyl, phenyl orp-nitrobenzyl group.
  • Suitable values for R 1 include hydrogen, hydroxy, OS0 3 H or a salt or methyl or ethyl ester thereof, methylthio, ethylthio, phenylthio, benzylthio, p-nitrobenzylthio, acetoxy, propionoxy, benzyloxy and phenylacetyloxy.
  • R 1 examples include hydrogen, hydroxy, acetoxy and OS0 3 H or a salt or methyl or ethyl ester thereof.
  • any sulphate moiety in the group R 1 in the compounds of the formula (I) is in the form of a quaternary ammonium salt, for example the benzyldimethyl-n-hexadecylammonium salt, or is in the form of a methyl or ethyl sulphate ester.
  • the compound of the formula (I) is in the form of a cleavable ester at the C-2 carboxyl.
  • Apt cleavable esters include those cleavable by chemical methods such as hydrogenolysis or hydrolysis or by biological methods.
  • the carboxylic acid is esterified by a group of the sub-formula (a), (b), (c) or (d): wherein R 4 is a hydrogen atom or an alkyl, alkenyl or alkynyl group of up to 3 carbon atoms; R 5 is a hydrogen atom or a methyl group; R 6 is a phenyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, methyl or methoxy group; R 7 is a hydrogen atom or a phenyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, methyl or methoxy group; R 8 is a hydrogen atom or a methyl group; R 9 is a (C 1-4 )alkyl, phenyl or (C 1-4 )alkoxy group or R 8 is joined to R 9 to form a phthalidyl, dimethylphthal
  • Favourably R 4 is a hydrogen atom or a methyl, ethyl, vinyl or ethenyl group.
  • Favourably R 5 is a hydrogen atom.
  • Favourably R 6 is a phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group.
  • Favourably R 7 is a hydrogen atom.
  • Favourably R 9 is a methyl, t-butyl or ethoxy group or is joined to R 8 .
  • Favourably R 10 is a methyl group.
  • Preferred groups of the sub-formula a) include the methyl and ethyl groups.
  • Preferred groups of the sub-formula b) include the benzyl and p-nitrobenzyl groups.
  • Preferred groups of the sub-formula c) include the acetoxymethyl, pivaloxyloxymethyl, a-ethoxycarbonyloxymethyl and phthalidyl groups.
  • a preferred group of the ⁇ sub-formula d) is the methoxymethyl group.
  • esterifying groups are the p-nitrobenzyl and phthalidyl groups.
  • the compound is in the form of an in-vivo hydrolysable ester or pharmaceutically acceptable salt.
  • Suitable in-vivo hydrolysable esters include those of sub-formula (c) as hereinbefore defined.
  • Suitable pharmaceutically acceptable salts include those of the alkali and alkaline earth metals; of these the sodium and potassium salts are preferred. These pharmaceutically acceptable salts may be formed at the C-2 carboxyl, and/or at a C-8 sulphate moiety (if present).
  • compounds of the formula (I) wherein R' is a OS0 3 H group or pharmaceutically acceptable salt thereof may be in the form of a di-salt such as the di-sodium salt or di-potassium salt, or may be in the form of a mono-salt of an in-vivo hydrolysable ester, or may be in the form of a mono-salt of an acid or may be in the form of a di-acid.
  • the compounds of the formula (I) may have the cis- or trans- geometry about the ⁇ -lactam, that is to say they have the (5R,6R) or (5R,6S) configuration.
  • the compounds of the formula (I) may be presented in the form of a cisltrans mixture.
  • the compounds of the formula (I) may have R or S stereochemistry at C-8 (except of course when R 1 is hydrogen) or may be in the form of mixtures thereof.
  • a compound of the formula (I) or salt or ester thereof is prepared from a starting material, which is a cleavable ester of a compound of the formula (II) defined above.
  • R 11 is a methyl group as the intermediates are more readily available.
  • the reaction is performed at a non-extreme temperature such as -15°C to +25°C, preferably ambient.
  • Solvents suitable in this reaction are inert organic solvents optionally in the presence of moisture, for example moist acetone or dioxan.
  • Preferred esters for use in this process are those described hereinbefore as preferred esters for compounds of the formula (I).
  • a particularly preferred ester for use in this process is the p-nitrobenzyl ester.
  • hypohalous acid is hypobromous acid or hypochlorous acid; of these hypobromous acid is preferred.
  • Suitable sources of hypohalous acids include N-bromoacetamide, N-chloroacetamide and N-bromopropionamide.
  • Compounds of the formula (II) may be prepared by the methods of European Patent Application Publication Numbers 0005348, 0005349, 0007152, 0008497, 0043197, Belgian Patent Number 864570, and U.K. Patent Number 1489235.
  • R 20 is a (C 1-6 )alkyl group
  • suitable substituents include amino, hydroxy, (C 1-6 )alkanoyloxy, (C 1-6 )alkoxy, benzoyl, (C 1-6 )alkanoyl, or carboxy or an ester or pharmaceutically acceptable salt thereof.
  • R 20 is a (C 3-6 )alkenyl group wherein the double bond is not present on the carbon adjacent to the sulphur atom
  • suitable substituents include carboxy or an ester or pharmaceutically acceptable salt thereof, hydroxy or (C 1-6 )alkoxy.
  • aralkyl means a (C 1-6 )alkyl group substituted by an aryl group, examples of such aryl groups being naphthyl, pyrrolyl, furyl, thienyl, indolyl, thionaphthyl, benzofuryl, imidazoyl, thiazolyl, or any of such groups substituted by one or more groups selected from (C 1 - 3 )alkyl, phenyl, nitro and amino; or a phenyl group optionally substituted by a halogen atom or a (C 1-3 )alkoxy, nitro or acetamido group.
  • a group of compounds of interest is that of the formula (IV): and pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof wherein R 14 is hydrogen, OS0 3 H or a pharmaceutically acceptable salt or a methyl or ethyl ester thereof, SR 3 , or OCONHR 3 where R 3 is a (C 1-4 )alkyl, benzyl, phenyl or p-nitrobenzyl group; and R 13 is (C 1-4 )alkyl; (C 1-4 )alkyl substituted by a phenyl group optionally substituted by fluorine, chlorine, bromine, methoxy, nitro, amino, acetamido or p-nitrobenzyloxycarbonylamino; (C 2-4 )alkyl substituted on other than the a-carbon atom by amino, p-nitro- benzyloxycarbonylamino, hydroxy, p-nitrobenzyloxycarbonyloxy, methoxy, acetoxy or (
  • R 22 in the compounds of the formula (VIII) is hydrogen or, especially, OS0 3 H or a pharmaceutically acceptable salt thereof, such as the sodium or potassium salt.
  • R 20 is an alkyl group or substituted alkyl group suitably such alkyl groups contain up to 4 carbon atoms
  • R 20 aptly may be methyl, ethyl, propyl, butyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxypropyl, methoxypropyl, methoxybutyl, acetoxymethyl, acetoxyethyl, propionoxy- methyl, propionoxyethyl, phenacyl, acetylmethyl, acetylethyl, propionylmethyl, propionylethyl, carboxymethyl or pharmaceutically acceptable salt thereof, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl
  • R 20 is an aralkyl group more suitably the alkyl moiety is a methylene or ethylene divalent radical.
  • Suitable examples of the aryl moiety are phenyl optionally substituted by one or more substituents selected from halogen, (C 1-3 )alkoxy, nitro or acetamido; pyrrolyl optionally substituted by phenyl or (C 1-3 )alkyl; thienyl optionally substituted by phenyl or (C 1-3 )alkyl; furyl optionally substituted by phenyl or (C 1 - 3 )alkyl; imidazolyl optionally substituted by one or more groups selected from phenyl, nitro, amino, (C 1 - 3 )alkyl; and thiazolyl optionally substituted by one or more groups selected from phenyl, nitro, amino and (C 1-3 )alkyl.
  • R 20 is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl, methoxybenzyl, nitrobenzyl, acetamidobenzyl, thiazolylmethyl, aminothiazolylmethyl, nitrothiazolylmethyl or phenylthizolylmethyl.
  • R 20 is phenethyl, pyrrolylethyl or optionally substituted imidazolyethyl.
  • the imidazolyl ring may be substituted at the C-2 position (that is the carbon atom a to the two nitrogen atoms) by (C 1-3 )alkyl or phenyl.
  • the imidazolyl ring may be further substituted at the C-4 position or the C-5 position by (C 1-3 )alkyl, phenyl, nitro or amino; preferably such substituents are at the C-4 position, and the C-5 position is unsubstituted; alternatively such substituents are at the C-5 position, and the C-4 position is unsubstituted.
  • R 20 is (C 1-6 )alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, for example acetyl, phenylacetyl, phenoxyacetyl or benzoyl. Of these, acetyl is preferred.
  • preferred compounds of the formula (VIII) include those of the formula (VI): or pharmaceutically acceptable salts or in-vivo hydrolysable esters thereof, wherein R 17 is OS0 3 H or a pharmaceutically acceptable salt or (C 1-4 )alkyl ester thereof, and R 18 is an optionally substituted (C 1-6 ) alkyl group.
  • Suitable and preferred in-vivo hydrolysable ester groups for esterifying the C-2 carboxyl of the compounds of the formulae (VIII) and (IV)-(VI) are those described in relation to compounds of the formula (I).
  • Suitable pharmaceutically acceptable salts of the compounds of the formulae (VIII) and (IV)-(VI) include those of the alkali and alkaline earth metals; of these, the sodium and potassium salts are preferred. These pharmaceutically acceptable salts may be formed at the C-2 carboxyl, and/or at a C-8 sulphate moiety (if present).
  • compounds of the formulae (VIII) and (IV)-(VI) wherein the C-6 substituent contains a OS0 3 H group or pharmaceutically acceptable salt thereof may be in the form of a di-salt such as the di- sodium or di-potassium salt, or may be in the form of a mono-salt of an in-vivo hydrolysable ester, or may be in the form of a di-acid.
  • the compounds of the formulae (VIII) and (IV) ⁇ (VI) are zwitterionic.
  • the compounds of the formulae (VIII) and (IV) ⁇ (VI) may have cis- or trans- geometry about the ⁇ -lactam, that is to say they have the (5R,6R) or (5R,6S) configuration.
  • the compounds of the formulae (VIII) and (IV)-(VI) may be presented in the form of a cis/trans mixture.
  • the compounds of the formulae (VIII) and (IV)-(VI) may have R or S stereochemistry at C-8 (except of course when the C-6 substituent is ethyl) or may be in the form of mixtures thereof.
  • the compounds of the formulae (VIII) and (IV)-(VI) wherein the C-6 substituent contains a OS0 3 H group or pharmaceutically acceptable salt thereof or (C 1-4 )alkyl ester thereof are suitably in the 8S-configuration as the necessary intermediates are more readily available.
  • Suitable acid acceptors for use in the process for preparing the compounds of the formula VIII are carbonates and bicarbonates such as anhydrous potassium carbonate.
  • the reaction is generally carried out in a dry polar solvent such as dimethylformamide.
  • the reaction is performed at a non-extreme temperature, for example, -30°C to +60°C, more suitably -10°C to +40°C; and preferably at ambient temperature.
  • X is a chlorine bromine or iodine atom or is a sulphonate ester moiety such as a toxylate or mesylate; of these values, iodine and chlorine are preferred.
  • R 20 is a methyl or ethyl group
  • the leaving group X may be dimethyl ether or diethyl ether respectively.
  • X is derived from a trimethyloxonium salt or a triethyloxonium salt. Such salts are conveniently presented as their tetrafluoroborates.
  • Such alkylations involving a trimethyloxonium or triethyloxonium salt are preferably performed in a halogenated hydrocarbon solvent, for example dichloromethane or chloroform, at a depressed temperature for example -80°C to 0°C, more suitably -70°C to -30°C.
  • a halogenated hydrocarbon solvent for example dichloromethane or chloroform
  • any amino group present can be conveniently protected in conventional manner, for example as a p-nitrobenzyloxy-carbonylamino group.
  • any hydroxy group present can be conveniently protected in conventional manner, for example as a p-nitrobenzyloxycarbonyloxy group.
  • 6-ethylidene compounds of the formula (XII): and salts and cleavable esters thereof are envisaged as intermediates in the processes mentioned above.
  • the compounds of the formula (XII) may be readily converted to 6-ethyl compounds by known processes such as reduction.
  • the processes of this invention are performed on hydrogenolysable esters, for example the p-nitrobenzyl ester, which may be cleaved using an approximately atmospheric pressure of hydrogen at ambient temperature with a transition metal catalyst for example palladium, preferably 5% or 10% palladium on carbon.
  • a transition metal catalyst for example palladium, preferably 5% or 10% palladium on carbon.
  • the compounds of the formulae (I) and (VIII) and their pharmaceutically acceptable salts and in-vivo hydrolysable esters may be employed in the treatment of bacterial infections such as those due to Staphylococcus aureus, Escherichia coli and Klebsiella aerogenes.
  • bacterial infections such as those due to Staphylococcus aureus, Escherichia coli and Klebsiella aerogenes.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formulae (IA) and salts and esters thereof and a pharmaceutically acceptable carrier.
  • compositions of this invention may be prepared by conventional methods of preparing antibiotic compositions and in conventional manner may be adapted for oral, topical or parenteral administration.
  • compositions of this invention are in the form of a unit-dose composition adapted for oral administration.
  • compositions of this invention are in the form of a unit dose composition adapted for administration by injection.
  • Unit-dose forms according to this invention will normally contain from 50 to 500 mg of a compound of this invention, for example about 62.5, 100, 125, 150, 200, 250 or 300 mg. Such compositions may be administered from 1 to 6 times a day or more conveniently 2, 3 or 4 times a day so that the total daily dose for a 70 kg adult is about 200 to 2000 mg, for example about 400, 600, 750, 1000 or 1500 mg.
  • compositions of this invention may be used to treat infections of the respiratory tract, urinary tract or soft tissues in humans, or mastitis in cattle.
  • the carriers used in the compositions of this invention may include diluents, binders, disintegrants, lubricants, colours, flavouring agents or preservatives in conventional manner.
  • suitable agents include lactose, starch, sucrose, calcium phosphate, sorbitol, polyvinylpyrrolidone, acacia, gelatin, tragacanth, potato starch or polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • compositions of this invention are most suitably in the form of unit-dose units such as tablets or capsules.
  • the present invention also provides synergistic pharmaceutical compositions which comprise a pharmaceutical composition as hereinbefore described which also contains a penicillin or a cephalosporin.
  • Suitable penicillins for inclusion in the compositions of this invention include benzyl penicillin, phenoxymethylpenicillin, ampicillin or a pro-drug therefor, amoxycillin or a pro-drug therefor, carbenicillin or a pro-drug therefor, ticarcillin or a pro-drug therefor, suncillin, sulbenicillin, azlocillin or mezlocillin.
  • penicillins for inclusion in orally administrable compositions of this invention include ampicillin and its orally administrable pro-drugs, amoxycillin and its orally administrable pro-drugs and orally administrable pro-drugs of carbenicillin.
  • penicillins include ampicillin anhydrate, ampicillin trihydrate, sodium ampicillin, talampicillin hydrochloride, pivampicillin hydrochloride and bacampicillin hydrochloride; amoxycillin trihydrate, sodium amoxycillin; and the sodium salts of the phenyl and 5-indanyl a-esters of carbenicillin.
  • a preferred penicillin for inclusion in the orally administrable compositions of this invention is amoxycillin trihydrate.
  • a further preferred penicillin for inclusion in the orally administrable compositions of this invention is ampicillin trihydrate.
  • Particularly suitable penicillins for inclusion in injectably administrable compositions of this invention include injectable salts such as the sodium salt of ampicillin, amoxycillin, carbenicillin and ticarcillin.
  • a preferred penicillin for inclusion in the injectably administrable compositions of this invention is sodium amoxycillin.
  • a further preferred penicillin for inclusion in the injectably administrable compositions of this invention is sodium ampicillin.
  • cephalosporins for inclusion in the compositions of this invention include cephaloridine, ⁇ ephaIexin, cephradine, cefazolin and cephalothin.
  • cephalexin is cephalexin
  • the weight ratio between compound of this invention and penicillin or cephalosporin is generally from 10:1 to 1:10, more usually from 5:1 to 1:5 and normally from 3:1 to 1:3.
  • the penicillin or cephalosporin is generally utilised in its conventionally administered amount.
  • Suitable methods of formulation include those described in the aforementioned European Patent Applications.
  • Example 1 a The product from Example 1 a was dissolved in DMF (1 ml) and to the solution was added anhydrous potassium carbonate (25 mg) and methyl iodide (0.2 ml). After stirring the mixture vigorously for 20 min, ethyl acetate (30 ml) was added, and the organic layer was washed with water (2 x 30 ml) and brine (30 ml). The solution was dried (MgS0 4 ) and the solvent evaporated in vacuo to leave a residue which was chromatographed on silica using 2% EtOH in CHCl 3 to elute. The title methylthio-derivative (e3) was obtained as a white solid (29 mg); V max.
  • Example 2a The product from Example 2a was dissolved in DMF (1 ml), and anhydrous potassium carbonate (20 mg) followed by methyl iodide (0.5 ml) were added to the solution. After stirring the mixture for 1.5 h, ethyl acetate (30 ml) was added and the organic solution was washed with water (2 x 30 ml) and brine (30 ml). The dried (MgSO 4 ) solution was concentrated in vacuo and the residue chromatographed on silica gel using 20% petroleum ether (60°-80°) in ethyl acetate to elute. The title methylthio-derivative (e6) was obtained as a gum (3 mg); v max.
  • Example 3a The product from Example 3a was treated with ethyl iodide (0.75 ml) and anhydrous K 2 CO 3 (250 mg) in DMF (5 ml) in a way analogous to that described in Example 1 b. Work-up as also described therein gave a product which was chromatographed on silica using a gradient elution with ethyl acetate/petroleum ether mixtures (from 80% to 100% ethyl acetate). The title ethylthio-derivative was obtained as a white crystalline solid (120 mgs); m.p. 180 ⁇ 183°; v max. (KBr) 3490,1760 and 1700 cm -1 ; ⁇ max.
  • the ester (e1) (200 mg) was converted into the thiol derivative (e2) by the method described in Example 1a.
  • the quaternary ammonium salt (e12) (660 mg) was converted into the thiol derivative (e13) by the method described in Example 4a.
  • Example 4a The product from Example 4a was dissolved in dry dichloromethane (15 ml) and to the solution was added anhydrous potassium carbonate (205 mg) and Meerwein's reagent (282 mg). The mixture was stirred for 15 min at room temperature and was then diluted with chloroform (30 ml). The organic solution was washed with very dilute brine, dried (MgS0 4 ) and concentrated in vacuo. Rapid chromatography of the residue on silica gel (230-400 ASTM) using 20% petroleum ether/ethyl acetate to elute afforded the title diester as a foam (189 mg); v mex.
  • silica gel 230-400 ASTM
  • the diester (e16) (60 mg) was stirred with anhydrous potassium carbonate (41 mg) in DMF (0.5 ml) at room temperature for 30 min. Ethyl acetate (30 ml) was added and the solution was washed with water (2 x 30 ml) and brine (20 ml) before drying (MgS0 4 ) and evaporating in vacuo. The product was chromatographed on silica gel using 30% petroleum ether in ethyl acetate to elute. The title ethylidene derivative (e17) was isolated as a gum; v max .
  • the quaternary ammonium salt (e12) (660 mg) was converted into the thiol (e13) by the method described in Example 4a.
  • the thiol derivative (e13) was treated with ethyl iodide and potassium carbonate in DMF in a manner analogous to that described in Example 4b.
  • the title ethylthio-derivative (e18) was otbained as a foam (240 mg); v max. (CHCI 3 ) 1780 and 1700 cm -1 ; ⁇ max. (EtOH) 317 and 267 nm.
  • the acetoxy derivative (e21) (90 mg) was dissolved in acetone (2 ml) containing water (3 drops). The solution was cooled to -20° and a solution of N-bromoacetamide in acetone (0.5 ml) was added with stirring. After 25 min at -20° the solution was diluted with chloroform (25 ml) and washed with water (25 ml). The organic layer was dried (MgS0 4 ) and concentrated in vacuo to afford a gum, which contained the thiol (e22), v max. (CHCI 3 ) 1780, 1730 and 1700 sh cm -1 .
  • the product (e22) was dissolved in pyridine (1 ml) and to the stirred solution was added acetyl chloride (3 drops). After 10 min the mixture was evaporated to dryness and the product was partitioned between chloroform (25 ml) and water (25 ml). The organic layer was washed with pH 3 phosphate buffer (20 ml), dilute aqueous sodium bicarbonate (20 ml) and water (20 ml), and then dried (MgS0 4 ) and concentrated in vacuo. The residue was chromatographed on silica gel using 50% petroleum ether-ethyl acetate to elute. The first-eluted component was the title diacetyl derivative (e23) (5 mg); v max.
  • the ester (e19) (1.12 g) was hydrogenolysed with 5% Pd-C (1.5 g) in 30% aqueous dioxan (100 ml) using the procedure of Example 6d. After work-up (190 mg NaHC0 3 ), as therein described, and chromatography on a column of Diaion HP20 (3.5 x 15 cm), eluting with water, fractions containing the product were combined and freeze-dried. The resulting solid (460 mg) consisted of the title disodium salt (e20); ⁇ max. (H 2 0) 300 nm (7900); v max.
  • Example 8 The method of Example 8 was used to convert the quaternaryammonium salt (e12) (2.8 g) into the thiol (e13), which was then alkylated with 1-(2-bromethyl) pyrrole.
  • the ester (e1, 500 mg, 1.119 mM) was dissolved in 1,4-dioxan (10 ml) containing water (30 drops). A solution of N-bromoacetamide (155 mg, 1.119 mM) in 1,4-dioxan was then added and the solution stirred at room temperature for 4.5 minutes. Chloroform (50 ml) was added and the organic phase was washed with pH 7.0, 0.05 M phosphate buffer, saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Filtration and removal of the solvent at reduced pressure yielded the crude thiol (e2) as a gum, v max. (CHCI 3 ) 1780, 1730 and 1700 cm -1 .
  • the title compound (e80) was prepared as a white solid in 20% yield from the ester (e28), adopting the procedure described in Example 13., m.p. 104 ⁇ 106°C (ethyl acetate/diethyl ether), ⁇ max. (EtOH) 317 nm (Em 12,360) 266 nm (Em 18,890); v max.
  • the ester (e80) was hydrogenolysed as in Example 13c to yield (5R,6R)-3-(3-aminopropylthio)-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (e81) in 26% yield as an aqueous solution (based on Em 8,500).
  • a sample was freeze dried to give a pale yellow fluffy solid, ⁇ max. (H 2 O) 292 nm, v max. (KBr) 3420, 1750, 1600 (broad) cm -1 .
  • the diester (e82) (150 mg) was prepared as a pale yellow solid by reaction of the ester (e1) (500 mg) with N-bromoacetamide, followed by p-nitrobenzyl bromoacetate, utilising the procedure outlined in Example 13., ⁇ max. (EtOH) 309 nm, 265 nm (Em 15,355); v max.
  • the diester (e84) (179 mg) was prepared as a pale yellow solid by reaction of the thiol (e40), derived from the ester (e28) (500 mg) with p-nitrobenzyl bromoacetate, by the method described in Example 13, ⁇ max. (EtOH) 311 nm (Em 11,120), 265 nm (Em 21,197); v max.
  • the diester (e84) (75 mg) was hydrogenolysed in the manner described in Example 15b. Biogel P-2 column chromatography, eluting with water afforded the title compound (e85) (15 mg) in aqueous solution, ⁇ max. (H 2 0) 300 nm. A sample was freeze dried to yield a yellow solid.
  • the title compound (e86) (97 mg) was prepared as a pale yellow solid by reacting the thiol (e2), derived from ester (e1) (500 mg) with 1-(ß-bromoethyl)-2-methyl-4-nitroimidazole, adopting the procedure described in Example 13, ⁇ max. (EtOH) 308 m, (Em 15449), 270 nm (Em 13539), v max.
  • the title compound (e93) was prepared by hydrogenolysis of the ester (e92) (30 mg)], following the procedure outlined in Example 13c with the exception that the hydrogenation time was extended to 4 hours. Freeze drying gave a white solid, ⁇ max. (H 2 0) 293 nm, v max. (KBr) 3400, 1750, 1600, 1390 cm- 1 .
  • the ester (e99) (90 mg) was hydrogenolysed, as in Example 13c, to yield the title compound (e100) (19 mg based on Em 17,000 at ⁇ max. 297 nm in the u.v. spectrum) as an aqueous solution.
  • a white fluffy solid was obtained on freeze-drying, ⁇ max. (H 2 0) 297 nm, v max. (KBr) 3400, 1740, 1600 cm- 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP82100683A 1979-08-10 1980-08-04 Beta-lactam antibiotics, their preparation and use Expired EP0055990B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB7927901 1979-08-10
GB7927901 1979-08-10
GB8012724 1980-04-17
GB8012724 1980-04-17

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EP0055990B1 true EP0055990B1 (en) 1986-06-11

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EP80302659A Expired EP0024832B1 (en) 1979-08-10 1980-08-04 Beta-lactam antibiotics, their preparation, pharmaceutical compositions containing them and their preparation

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ES (2) ES8106308A1 (index.php)
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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0072121A1 (en) * 1981-08-08 1983-02-16 Beecham Group Plc Beta-lactam antibiotics
US4552873A (en) * 1981-08-19 1985-11-12 Sankyo Company Limited Carbapenem compounds, and compositions containing them
EP0079167A1 (en) * 1981-11-09 1983-05-18 Beecham Group Plc A carbapenem compound, preparation and use
GB2116540B (en) * 1981-11-10 1985-07-17 Shionogi & Co Pluracidomycin b c and d and analogs thereof their production and a microorganism for use therein
US4556517A (en) * 1981-12-29 1985-12-03 Shionogi & Co., Ltd. Carbapenem derivatives
DE3372773D1 (de) * 1982-03-26 1987-09-03 Hoechst Uk Ltd 7-oxo-4-thia-1-azabicyclo(3,2,0)heptane derivatives
US4683301A (en) * 1982-04-08 1987-07-28 Bristol-Myers Company Carbapenem antibiotics
US4710568A (en) * 1982-04-09 1987-12-01 Bristol-Myers Company Carbapenem antibiotics
US4642341A (en) * 1982-04-09 1987-02-10 Bristol-Myers Company Carbapenem antibiotics
US4536335A (en) * 1982-06-18 1985-08-20 Bristol-Myers Company Carbapenem antibiotics
US4665170A (en) * 1982-06-18 1987-05-12 Bristol-Myers Company Carbapenem antibiotics
US4640799A (en) * 1982-06-18 1987-02-03 Bristol-Myers Company Carbapenem antibiotics
US4732977A (en) * 1982-09-28 1988-03-22 Bristol Myers Company Carbapenem antibiotics
US4746736A (en) * 1982-09-28 1988-05-24 Bristol-Myers Company Carbapenem antibiotics
EP0345827A1 (en) * 1982-11-29 1989-12-13 Schering Corporation Process for the production of penem compounds
US4698339A (en) * 1983-09-28 1987-10-06 Takeda Chemical Industries, Ltd. Carbapenems, their production and use
EP0137403A3 (en) * 1983-09-28 1987-04-15 Takeda Chemical Industries, Ltd. Carbapenems, their production and use
ZA848416B (en) * 1983-11-10 1986-06-25 Dow Chemical Co Fluorophenoxy compounds,herbicidal compositions and methods
US4717728A (en) * 1983-11-21 1988-01-05 Merck & Co., Inc. Cyclic amidinyl and cyclic guanidinyl thio carbapenems

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017992A1 (en) * 1979-04-19 1980-10-29 Merck & Co. Inc. 2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1531141A (en) * 1976-08-17 1978-11-01 Beecham Group Ltd Beta-lactam antibiotics
NL7802826A (nl) * 1977-04-08 1978-10-10 Merck & Co Inc Thienamycinederivaat, werkwijze voor het bereiden daarvan, alsmede farmaceutische preparaten.
US4235917A (en) * 1977-05-05 1980-11-25 Merck & Co., Inc. N-Alkyl-N-acyl derivatives of thienamycin
EP0001567B1 (en) * 1977-10-13 1981-12-02 Sanraku-Ocean Co., Ltd. Thienamycin related antibiotics ps-6 and ps-7, process for their production and compositions containing them
US4347367A (en) * 1977-10-19 1982-08-31 Merck & Co., Inc. 3-Substituted-6-(1'-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid
US4347368A (en) * 1977-10-19 1982-08-31 Merck & Co., Inc. 3-Substituted-6-substituted-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
AU4061378A (en) * 1977-10-19 1980-04-17 Merck & Co., Inc. 1-azabicyclo (3.2.0) hept-2-enes
EP0030392B1 (en) * 1978-01-19 1984-05-16 Beecham Group Plc Intermediates for use in the preparation of carbapenems
EP0004132A1 (en) * 1978-03-04 1979-09-19 Beecham Group Plc Esters of beta-lactam antibiotics, a process for their preparation pharmaceutical compositions containing them and the compounds for use as antibacterial agents
US4203902A (en) * 1978-04-21 1980-05-20 Merck & Co., Inc. Process for preparing 6- and 2-substituted-1-carbadethiapen-2-em-3-carboxylic acids
DE2963717D1 (en) * 1978-05-06 1982-11-04 Beecham Group Plc Carbapenem derivatives, a process for their preparation and pharmaceutical compositions containing them
EP0005349A1 (en) * 1978-05-06 1979-11-14 Beecham Group Plc Alkylcarbapenems, their preparation, use in pharmaceutical compositions and intermediates
DE2963580D1 (en) * 1978-08-02 1982-10-21 Beecham Group Plc Beta-lactam antibacterial agents, a process for their preparation and pharmaceutical compositions containing them
DE2966187D1 (en) * 1978-08-23 1983-10-27 Beecham Group Plc Beta-lactam antibacterial compounds, their preparation and pharmaceutical compositions containing them
DE2961882D1 (en) * 1978-08-25 1982-03-04 Beecham Group Plc Beta-lactam anti-bacterials, compositions containing them and a process for their preparation
EP0008885B1 (en) * 1978-09-09 1983-11-30 Beecham Group Plc Beta-lactam compounds, their preparation and use
DE2965394D1 (en) * 1978-11-01 1983-06-16 Sanraku Ocean Co Process for producing antibiotic beta-lactam compounds
US4376774A (en) * 1979-05-29 1983-03-15 Merck & Co., Inc. Antibiotic N-heterocyclyl thienamycin

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017992A1 (en) * 1979-04-19 1980-10-29 Merck & Co. Inc. 2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates

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CA1175841A (en) 1984-10-09
AU6119680A (en) 1981-02-12
FI802446A7 (fi) 1981-01-01
IL60758A0 (en) 1980-10-26
NZ194584A (en) 1983-05-31
ES494136A0 (es) 1981-08-01
GR69935B (index.php) 1982-07-21
ES499856A0 (es) 1982-01-16
EP0024832A1 (en) 1981-03-11
NO802377L (no) 1981-02-11
EP0024832B1 (en) 1985-03-13
ES8106308A1 (es) 1981-08-01
ES8202010A1 (es) 1982-01-16
DK344080A (da) 1981-02-11
DE3070269D1 (en) 1985-04-18
EP0055990A1 (en) 1982-07-14
US4473578A (en) 1984-09-25

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